tbuckley/cabot-search huggingface dataset:
Activation of MAP2K signaling by genetic engineering or HF-rTMS promotes corticospinal axon sprouting and functional regeneration
Authors: Francesco Boato, Xiaofei Guan, Yanjie Zhu, Youngjae Ryu, Mariel Voutounou, Christopher Rynne, Chase R. Freschlin, Paul Zumbo, Doron Betel, Katie Matho, Sergey N. Makarov, Zhuhao Wu, Young-Jin Son, Aapo Nummenmaa, Josh Z. Huang, Dylan J. Edwards, Jian Zhong
Journal: Science Translational Medicine (2023)

Facilitating axon regeneration in the injured central nervous system remains a challenging task. RAF-MAP2K signaling plays a key role in axon elongation during nervous system development. Here, we show that conditional expression of a constitutively kinase-activated BRAF in mature corticospinal neurons elicited the expression of a set of transcription factors previously implicated in the regeneration of zebrafish retinal ganglion cell axons and promoted regeneration and sprouting of corticospinal tract (CST) axons after spinal cord injury in mice. Newly sprouting axon collaterals formed synaptic connections with spinal interneurons, resulting in improved recovery of motor function. Noninvasive suprathreshold high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) activated the BRAF canonical downstream effectors MAP2K1/2 and modulated the expression of a set of regeneration-related transcription factors in a pattern consistent with that induced by BRAF activation. HF-rTMS enabled CST axon regeneration and sprouting, which was abolished in MAP2K1/2 conditional null mice. These data collectively demonstrate a central role of MAP2K signaling in augmenting the growth capacity of mature corticospinal neurons and suggest that HF-rTMS might have potential for treating spinal cord injury by modulating MAP2K signaling.
USP1-regulated reciprocal differentiation of Th17 cells and Treg cells by deubiquitinating and stabilizing TAZ
Authors: Xiaotong Zhu, Peng Wang, Xiaoxia Zhan, Yuping Zhang, Junli Sheng, Shitong He, Yitian Chen, Dingnai Nie, Xiaolong You, Haiyan Mai, Qinghong Yu, Laisheng Li, Ligang Jie, Shengfeng Hu
Journal: Cellular and Molecular Immunology (2023)
Moving the Dial on Airway Inflammation in Response to Trikafta in Adolescents with Cystic Fibrosis
Authors: Agathe Lepissier, Anne Sophie Bonnel, Nathalie Wizla, Laurence Weiss, Marie Mittaine, Katia Bessaci, Eitan Kerem, Véronique Houdouin, Philippe Reix, Christophe Marguet, Isabelle Sermet-Gaudelus
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

"Moving the Dial on Airway Inflammation in Response to Trikafta® in Adolescents with Cystic Fibrosis ." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp. –
Pregnancy outcomes in women with sickle cell disease in California
Authors: Oyebimpe O. Adesina, Ann Brunson, Samantha C. Fisch, Bo Yu, Anjlee Mahajan, Shaina M. Willen, Theresa H. M. Keegan, Ted Wun
Journal: American Journal of Hematology (2023)

Adverse pregnancy outcomes occur frequently in women with sickle cell disease (SCD) across the globe. In the United States, Black women experience disproportionately worse maternal health outcomes than all other racial groups. To better understand how social determinants of health impact SCD maternal morbidity, we used California's Department of Health Care Access and Information data (1991-2019) to estimate the cumulative incidence of pregnancy outcomes in Black women with and without SCD-adjusted for age, insurance status, and Distressed Community Index (DCI) scores. Black pregnant women with SCD were more likely to deliver at a younger age, use government insurance, and live in at-risk or distressed neighborhoods, compared to those without SCD. They also experienced higher stillbirths (26.8, 95% confidence interval [CI]: 17.5-36.1 vs. 12.4 [CI: 12.1-12.7], per 1000 births) and inpatient maternal mortality (344.5 [CI: 337.6-682.2] vs. 6.1 [CI: 2.3-8.4], per 100 000 live births). Multivariate logistic regression models showed Black pregnant women with SCD had significantly higher odds ratios (OR) for sepsis (OR 14.89, CI: 10.81, 20.52), venous thromboembolism (OR 13.60, CI: 9.16, 20.20), and postpartum hemorrhage (OR 2.25, CI 1.79-2.82), with peak onset in the second trimester, third trimester, and six weeks postpartum, respectively. Despite adjusting for sociodemographic factors, Black women with SCD still experienced significantly worse pregnancy outcomes than those without SCD. We need additional studies to determine if early introduction to reproductive health education, continuation of SCD-modifying therapies during pregnancy, and increasing access to multidisciplinary perinatal care can reduce morbidity in pregnant women with SCD.
Vaccination with S <sub>pan</sub> , an antigen guided by SARS-CoV-2 S protein evolution, protects against challenge with viral variants in mice
Authors: Yongliang Zhao, Wenjia Ni, Simeng Liang, Lianghui Dong, Min Xiang, Zeng Cai, Danping Niu, Qiuhan Zhang, Dehe Wang, Yucheng Zheng, Zhen Zhang, Dan Zhou, Wenhua Guo, Yongbing Pan, Xiaoli Wu, Yimin Yang, Zhaofei Jing, Yongzhong Jiang, Yu Chen, Huan Yan, Yu Zhou, Ke Xu, Ke Lan
Journal: Science Translational Medicine (2023)

SARS-CoV-2 continues to accumulate mutations to evade immunity, leading to breakthrough infections after vaccination. How researchers can anticipate the evolutionary trajectory of the virus in advance in the design of next-generation vaccines requires investigation. Here, we performed a comprehensive study of 11,650,487 SARS-CoV-2 sequences, which revealed that the SARS-CoV-2 spike (S) protein evolved not randomly but into directional paths of either high infectivity plus low immune resistance or low infectivity plus high immune resistance. The viral infectivity and immune resistance of variants are generally incompatible, except for limited variants such as Beta and Kappa. The Omicron variant has the highest immune resistance but showed high infectivity in only one of the tested cell lines. To provide cross-clade immunity against variants that undergo diverse evolutionary pathways, we designed a new pan-vaccine antigen (S pan ). S pan was designed by analyzing the homology of 2675 SARS-CoV-2 S protein sequences from the NCBI database before the Delta variant emerged. The refined S pan protein harbors high-frequency residues at given positions that reflect cross-clade generality in sequence evolution. Compared with a prototype wild-type (S wt ) vaccine, which, when administered to mice, induced serum with decreased neutralization activity against emerging variants, S pan vaccination of mice elicited broad immunity to a wide range of variants, including those that emerged after our design. Moreover, vaccinating mice with a heterologous S pan booster conferred complete protection against lethal infection with the Omicron variant. Our results highlight the importance and feasibility of a universal vaccine to fight against SARS-CoV-2 antigenic drift.
Intestinal epithelial HDAC3 and MHC class II coordinate microbiota-specific immunity
Authors: Emily M. Eshleman, Tzu-Yu Shao, Vivienne Woo, Taylor Rice, Laura Engleman, Bailey J. Didriksen, Jordan Whitt, David B. Haslam, Sing Sing Way, Theresa Alenghat
Journal: Journal of Clinical Investigation (2023)

Aberrant immune responses to resident microbes promote inflammatory bowel disease and other chronic inflammatory conditions. However, how microbiota-specific immunity is controlled in mucosal tissues remains poorly understood. Here, we found that mice lacking epithelial expression of microbiota-sensitive histone deacetylase 3 (HDAC3) exhibited increased accumulation of commensal-specific CD4+ T cells in the intestine, provoking the hypothesis that epithelial HDAC3 may instruct local microbiota-specific immunity. Consistent with this, microbiota-specific CD4+ T cells and epithelial HDAC3 expression were concurrently induced following early-life microbiota colonization. Further, epithelium-intrinsic ablation of HDAC3 decreased commensal-specific Tregs, increased commensal-specific Th17 cells, and promoted T cell–driven colitis. Mechanistically, HDAC3 was essential for NF-κB–dependent regulation of epithelial MHC class II (MHCII). Epithelium-intrinsic MHCII dampened local accumulation of commensal-specific Th17 cells in adult mice and protected against microbiota-triggered inflammation. Remarkably, HDAC3 enabled the microbiota to induce MHCII expression on epithelial cells and limit the number of commensal-specific T cells in the intestine. Collectively, these data reveal a central role for an epithelial histone deacetylase in directing the dynamic balance of tissue-intrinsic CD4+ T cell subsets that recognize commensal microbes and control inflammation.
Cuplike nuclei in B-cell acute lymphoblastic leukemia with <i>DUX4</i> rearrangement
Authors: Maxime Heuchon, Margaux Wiber
Journal: Blood (2023)

An 11-year-old girl presented with a 1-month history of weakness, headaches, and fever episodes.Complete blood count showed anemia (hemoglobin, 41 g/L), leukopenia (3.44 × 10 9 /L), neutropenia (0.77 × 10 9 /L), and 25% blasts with frequent (80%) cuplike nuclei (panels A-D; arrowheads; original magnification ×1000; May-Grünwald-Giemsa stain).Flow cytometry showed coexpression of CD19, CD10, and CD34 consistent with a common B-cell acute lymphoblastic leukemia (B-ALL).Bone marrow aspiration showed 90% lymphoblasts with a less conspicuous and less frequent (40%) cuplike nuclei than in blood (panels E-F; arrowheads; original magnification ×1000; May-Grünwald-Giemsa stain).Karyotype was normal (46,XX).Targeted next-generation sequencing showed pathogenic variants in IKZF1 (p.R213Stop), FLT3 (p.M578delinsIP), and TP53 (p.R248W).Moreover, IKZF1 and ERG deletions were found leading to highlight an IGH::DUX4 fusion by targeted RNA sequencing.
Determinants of survival and retrospective comparisons of 183 clinical trial patients with myelofibrosis treated with momelotinib, ruxolitinib, fedratinib or BMS- 911543 JAK2 inhibitor
Authors: Naseema Gangat, Kebede H. Begna, Aref Al-Kali, William Hogan, Mark Litzow, Animesh Pardanani, Ayalew Tefferi
Journal: Blood Cancer Journal (2023)

Between October 2007 and July 2013, 183 Mayo Clinic patients (median age 65 years; 58% males) with high/intermediate risk myelofibrosis (MF) were enrolled in consecutive phase 1/2 JAK2 inhibitor (JAKi) clinical trials with momelotinib (n = 79), ruxolitinib (n = 50), fedratinib (n = 23) and BMS-911543 (n = 31). Using conventional criteria, the respective response rates for spleen and "transfusion-dependent anemia" were 47%, 32%, 83%, 62% and 51%, 30%, 10%, 44%, respectively, favoring momelotinib for anemia response (p = 0.02) and fedratinib for spleen response (p < 0.01). All study patients were followed to death or 2022, during which time 177 (97%) drug discontinuations, 27 (15%) leukemic transformations, and 22 (12%) allogeneic stem cell transplants (ASCT) were recorded. 5/10-year survival rate for all 183 patients was 41%/16% and not significantly different across the four drug cohorts (p = 0.33). Multivariable analysis of pre-treatment variables identified age >65 years (HR 3.5), absence of type 1/like CALR mutation (HR 2.8), baseline transfusion need (HR 2.1), and presence of ASXL1/SRSF2 mutation (HR 1.6) as risk factors for overall survival; subsequent HR-based modeling segregated three risk categories with 5/10-year survival rates of 84%/60%, 44%/14%, and 21%/5% (p < 0.01). In addition, spleen (p < 0.01) and anemia (p = 0.01) responses were independently associated with improved short-term survival while long-term survival was secured only by ASCT (5/10-year survival rate 91%/45% vs 47%/19% in non-transplanted patients; p < 0.01). The current retrospective study suggests the value of specific pre-treatment variables in identifying long-lived MF patients receiving JAKi and also confirms recent observations on the favorable impact of treatment response on short-term and of ASCT on long-term survival.
Multiple Cerebral Hemorrhages in a Patient Receiving Lecanemab and Treated with t-PA for Stroke
Authors: Nicholas J Reish, Pouya Jamshidi, Brian Stamm, Margaret E Flanagan, Elizabeth Sugg, Mengxuan Tang, Kelly L Donohue, Matthew McCord, Chase Krumpelman, Marek-Marsel Mesulam, Rudolph Castellani, Sherry H-Y Chou
Journal: New England Journal of Medicine (2023)
Price Transparency in Hospitals—Current Research and Future Directions
Authors: John Xuefeng Jiang, Ranjani Krishnan, Ge Bai
Journal: JAMA Network Open (2023)

Zeynep G. Gul, MD; Danielle R. Sharbaugh, MPH; Cailey J. Guercio, MD; Daniel L. Pelzman, MD; Cameron A. Jones, MD; Emily C. Hacker, BS; Vivian I. Anyaeche, BS; Levi Bowers, BS; Ashti M. Shah, BS; Michael G. Stencel, MD; Jonathan G. Yabes, PhD; Bruce L. Jacobs, MD, MPH; Benjamin J. Davies, MD
Development and Validation of a Genomic Profile for the Omission of Local Adjuvant Radiation in Breast Cancer
Authors: Martin Sjöström, Anthony Fyles, Fei-Fei Liu, David McCready, Wei Shi, Katrina Rey-McIntyre, S. Laura Chang, Felix Y. Feng, Corey W. Speers, Lori J. Pierce, Erik Holmberg, Mårten Fernö, Per Malmström, Per Karlsson
Journal: Journal of Clinical Oncology (2023)

PURPOSE Adjuvant radiotherapy (RT) is used for women with early-stage invasive breast cancer treated with breast-conserving surgery. However, some women with low risk of recurrence may safely be spared RT. This study aimed to identify these women using a molecular-based approach. METHODS We analyzed two randomized trials of women with node-negative invasive breast cancer to ± RT following breast-conserving surgery: SweBCG91-RT (stage I-II, no adjuvant systemic therapy) and Princess Margaret (age 50 years or older, T1-T2, adjuvant tamoxifen). Transcriptome-wide profiling was performed (Affymetrix Human Exon 1.0 ST microarray). Patients with estrogen receptor–positive/human epidermal growth factor receptor 2–negative tumors and with gene expression data were included. The SweBCG91-RT cohort was divided into training (N = 243) and validation (N = 354) cohorts. A 16-gene signature named Profile for the Omission of Local Adjuvant Radiation (POLAR) was trained to predict locoregional recurrence (LRR) using elastic net regression. POLAR was then validated in the SweBCG91-RT validation cohort and the Princess Margaret cohort (N = 132). RESULTS Patients categorized as POLAR low-risk without RT had a 10-year LRR of 6% (95% CI, 2 to 16) and 7% (0 to 27) in SweBCG91-RT and Princess Margaret cohorts, respectively. There was no significant benefit from RT in POLAR low-risk patients (hazard ratio [HR], 1.1 [0.39 to 3.4], P = .81, and HR, 1.5 [0.14 to 16], P = .74, respectively). Patients categorized as POLAR high-risk had a significant decreased risk of LRR with RT (HR, 0.43 [0.24 to 0.78], P = .0055, and HR, 0.25 [0.07 to 0.92], P = .038, respectively). An exploratory analysis testing for interaction between RT and POLAR in the combined validation cohort was performed ( P = .066). CONCLUSION The novel POLAR genomic signature on the basis of LRR biology may identify patients with a low risk of LRR despite not receiving RT, and thus may be candidates for RT omission.
Long-Term Air Pollution, Genetic Susceptibility, and the Risk of Depression and Anxiety: A Prospective Study in the UK Biobank Cohort
Authors: Xu Gao, Meijie Jiang, Ninghao Huang, Xinbiao Guo, Tao Huang
Journal: Environmental Health Perspectives (2023)

Background: Depression and anxiety are two mental disorders that are often comorbid. However, the associations of long-term air pollution exposure with depression and anxiety remain inconclusive. Objective: We conducted a cross-sectional and prospective study to examine the associations of ambient exposure to particulate matter (PM) with a diameter of ≤2.5μm (PM2.5), ≤10μm (PM10), and 2.5–10μm (PMcoarse), nitrogen oxides (NOx), and nitrogen dioxide (NO2) with the risk of depression and anxiety in the UK Biobank. Methods: This study included 398,241 participants from the UK Biobank, 128,456 of whom participated the 7-y online mental health survey. A total of 345,876 individuals were free of depression and anxiety at baseline; of those, 16,185 developed incident mental disorders during a median of 8.7 y of follow-up. Depression and anxiety were assessed using hospital admission records and mental health questionnaires. Associations of air pollution with prevalent and incident mental disorders were examined using logistic regression and Cox regression models, respectively. Results: Elevated levels of the five air pollutants were associated with higher odds of mental disorders at baseline. Levels of four pollutants but not PMcoarse were also associated with higher odds and risks of mental disorders during follow-up; specifically, hazard ratios [HR, 95% confidence interval (CI)] of an interquartile range increase in PM2.5, PM10, NOx, and NO2 for incident mental disorders were 1.03 (95% CI: 1.01, 1.05), 1.06 (95% CI: 1.04, 1.08), 1.03 (95% CI: 1.01, 1.05), and 1.06 (95% CI: 1.04, 1.09), respectively. An air pollution index reflecting combined effects of pollutants also demonstrated a positive association with the risk of mental disorders. HR (95% CI) of incident mental disorders were 1.11 (95% CI: 1.05, 1.18) in the highest quintile group in comparison with the lowest quintile of the air pollution index. We further observed that the associations between air pollution and mental disorders differed by a genetic risk score based on single nucleotide polymorphisms previously associated with genetic susceptibility to mental disorders in the UK Biobank cohort. Discussion: To our knowledge, this research is one of the largest cohort studies that demonstrates an association between mental health disorders and exposure to long-term air pollution, which could be further enhanced by genetic predisposition. https://doi.org/10.1289/EHP10391
Prostate cancer risk, screening and management in patients with germline BRCA1/2 mutations
Authors: Pawel Rajwa, Fahad Quhal, Benjamin Pradere, Giorgio Gandaglia, Guillaume Ploussard, Michael S. Leapman, John L. Gore, Andrzej Paradysz, Derya Tilki, Axel S. Merseburger, Todd M. Morgan, Alberto Briganti, Ganesh S. Palapattu, Shahrokh F. Shariat
Journal: Nature Reviews Urology (2023)
The development of a cSMART-based integrated model for hepatocellular carcinoma diagnosis
Authors: Tong Wu, Rong Fan, Jian Bai, Zhao Yang, Yun-Song Qian, Lu-Tao Du, Chun-Ying Wang, Ying-Chao Wang, Guo-Qing Jiang, Dan Zheng, Xiao-Tang Fan, Bo Zheng, Jing-Feng Liu, Guo-Hong Deng, Feng Shen, He-Ping Hu, Yi-Nong Ye, Qing-Zheng Zhang, Jing Zhang, Yan-Hang Gao, Jie Xia, Hua-Dong Yan, Min-Feng Liang, Yan-Long Yu, Fu-Ming Sun, Yu-Jing Gao, Jian Sun, Chun-Xiu Zhong, Yin Wang, Hui Wang, Fei Kong, Jin-Ming Chen, Hao Wen, Bo-Ming Wu, Chuan-Xin Wang, Lin Wu, Jin-Lin Hou, Xiao-Long Liu, Hong-Yang Wang, Lei Chen
Journal: Journal of Hematology & Oncology (2023)

Abstract Background Hepatocellular carcinoma (HCC) generally arises from a background of liver cirrhosis (LC). Patients with cirrhosis and suspected HCC are recommended to undergo serum biomarker tests and imaging diagnostic evaluation. However, the performance of routine diagnostic methods in detecting early HCC remains unpromising. Methods Here, we conducted a large-scale, multicenter study of 1675 participants including 490 healthy controls, 577 LC patients, and 608 HCC patients from nine clinical centers across nine provinces of China, profiled gene mutation signatures of cell-free DNA (cfDNA) using Circulating Single-Molecule Amplification and Resequencing Technology (cSMART) through detecting 931 mutation sites across 21 genes. Results An integrated diagnostic model called “Combined method” was developed by combining three mutation sites and three serum biomarkers. Combined method outperformed AFP in the diagnosis of HCC, especially early HCC, with sensitivities of 81.25% for all stages and 66.67% for early HCC, respectively. Importantly, the integrated model exhibited high accuracy in differentiating AFP-negative, AFP-L3-negative, and PIVKA-II-negative HCCs from LCs.
A Stormy Heart
Authors: Allison Kratka, Usha B. Tedrow, Richard N. Mitchell, Amy L. Miller, Joseph Loscalzo
Journal: New England Journal of Medicine (2023)

A 68-year-old woman with a history of hypertension and obstructive sleep apnea presented to the emergency department with palpitations, lightheadedness, and dyspnea. She had a 2-year history of intermittent palpitations.
Prognostic models for mortality risk in patients requiring ECMO
Authors: Lara C. A. Pladet, Jaimie M. M. Barten, Lisette M. Vernooij, Carlos V. Elzo Kraemer, Jeroen J. H. Bunge, Erik Scholten, Leon J. Montenij, Marijn Kuijpers, Dirk W. Donker, Olaf L. Cremer, Christiaan L. Meuwese
Journal: Intensive Care Medicine (2023)

To provide an overview and evaluate the performance of mortality prediction models for patients requiring extracorporeal membrane oxygenation (ECMO) support for refractory cardiocirculatory or respiratory failure.A systematic literature search was undertaken to identify studies developing and/or validating multivariable prediction models for all-cause mortality in adults requiring or receiving veno-arterial (V-A) or veno-venous (V-V) ECMO. Estimates of model performance (observed versus expected (O:E) ratio and c-statistic) were summarized using random effects models and sources of heterogeneity were explored by means of meta-regression. Risk of bias was assessed using the Prediction model Risk Of BiAS Tool (PROBAST).Among 4905 articles screened, 96 studies described a total of 58 models and 225 external validations. Out of all 58 models which were specifically developed for ECMO patients, 14 (24%) were ever externally validated. Discriminatory ability of frequently validated models developed for ECMO patients (i.e., SAVE and RESP score) was moderate on average (pooled c-statistics between 0.66 and 0.70), and comparable to general intensive care population-based models (pooled c-statistics varying between 0.66 and 0.69 for the Simplified Acute Physiology Score II (SAPS II), Acute Physiology and Chronic Health Evaluation II (APACHE II) score and Sequential Organ Failure Assessment (SOFA) score). Nearly all models tended to underestimate mortality with a pooled O:E > 1. There was a wide variability in reported performance measures of external validations, reflecting a large between-study heterogeneity. Only 1 of the 58 models met the generally accepted Prediction model Risk Of BiAS Tool criteria of good quality. Importantly, all predicted outcomes were conditional on the fact that ECMO support had already been initiated, thereby reducing their applicability for patient selection in clinical practice.A large number of mortality prediction models have been developed for ECMO patients, yet only a minority has been externally validated. Furthermore, we observed only moderate predictive performance, large heterogeneity between-study populations and model performance, and poor methodological quality overall. Most importantly, current models are unsuitable to provide decision support for selecting individuals in whom initiation of ECMO would be most beneficial, as all models were developed in ECMO patients only and the decision to start ECMO had, therefore, already been made.